Oncogenic transforming sequences, termed oncogenes, have been detected in the DNAs of a variety of human tumors. These oncogenes have been assayed experimentally by the procedure of gene transfer (transfection), since they are able to induce transformation of recipient cells. Several distinct human oncogenes have been characterized and/or isolated as molecular clones. Three of these oncogenes are related to oncogenes carried by rat Kirsten or Harvey sarcoma viruses. These oncogenes are consequently members of the ras gene family. Each oncogene appears to derive via somatic mutation from a normal cellular gene termed a proto-oncogene. The Kirsten ras-related oncogene, termed cKi-ras2, is of particular interest, since it has been implicated in a variety of commonly occurring human tumors including carcinomas of the colon and lung. Molecular isolation of this important oncogene has been impeded by its large size and by the presence of sequences that inhibit molecular cloning. An alternative approach for oncogene isolation is proposed here. Since the important lesions creating the oncogene appear to affect protein-encoding sequences, a strategy for the rapid retrieval of cDNA clones of these genes is proposed. This involves construction of a chimeric retrovirus vector designed to retrieve the desired Ki-ras2 sequences from human tumor cells or derived transfected cells. In addition, a second chimeric virus, carrying an intact Harvey ras (cHa-ras1) proto-oncogene will be used to experimentally generate a group of independently activated oncogenic alleles. These naturally existing (cKi-ras2) or experimentally created (cHa-ras1) oncogenic alleles will be compared to explore the hypothesis that they are functionally different from one another and have distinct effects on tumor cell phenotype and consequent progression of tumor growth. The experimental system will also be exploited to attempt activation of the proto-oncogenes by known carcinogens, thus exploring the interaction of these agents with an important cellular target.